Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP)-targeted delivery of soluble TRAIL potently inhibits melanoma outgrowth in vitro and in vivo

Molecular Cancer

Research

Rudi AJO Dierckx¹  Anna A Rybczynska¹  Aren van Waarde¹  Michael Schwenkert²  Georg H Fey²  Wijnand Helfrich³  Edwin Bremer³  Marco de Bruyn³  Yunwei Wei⁴ 

[1] Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen (Hanzeplein 1), University of Groningen, (9713 GZ), Groningen, The Netherlands;Genetics, University of Erlangen Nuremberg, Erwin Rommel Strasse 3, (91058), Erlangen, Germany;Surgical Research Laboratories, Department of Surgery, University Medical Center Groningen (Hanzeplein 1), University of Groningen, (9713 GZ), Groningen, The Netherlands;Surgical Research Laboratories, Department of Surgery, University Medical Center Groningen (Hanzeplein 1), University of Groningen, (9713 GZ), Groningen, The Netherlands;Third department of General Surgery, First Clinical Hospital of Harbin, Medical University Harbin, 23 Youzheng Street, (150001), Harbin, China;

关键词: Melanoma;    Melanoma Cell;    Focal Adhesion Kinase;    Pentazocine;    Trail Treatment;   

DOI  :  10.1186/1476-4598-9-301

 received in 2010-05-26, accepted in 2010-11-23,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundAdvanced melanoma is characterized by a pronounced resistance to therapy leading to a limited patient survival of ~6 - 9 months. Here, we report on a novel bifunctional therapeutic fusion protein, designated anti-MCSP:TRAIL, that is comprised of a melanoma-associated chondroitin sulfate proteoglycan (MCSP)-specific antibody fragment (scFv) fused to soluble human TRAIL. MCSP is a well-established target for melanoma immunotherapy and has recently been shown to provide important tumorigenic signals to melanoma cells. TRAIL is a highly promising tumoricidal cytokine with no or minimal toxicity towards normal cells. Anti-MCSP:TRAIL was designed to 1. selectively accrete at the cell surface of MCSP-positive melanoma cells and inhibit MCSP tumorigenic signaling and 2. activate apoptotic TRAIL-signaling.ResultsTreatment of a panel of MCSP-positive melanoma cell lines with anti-MCSP:TRAIL induced TRAIL-mediated apoptotic cell death within 16 h. Of note, treatment with anti-MCSP:sTRAIL was also characterized by a rapid dephosphorylation of key proteins, such as FAK, implicated in MCSP-mediated malignant behavior. Importantly, anti-MCSP:TRAIL treatment already inhibited anchorage-independent growth by 50% at low picomolar concentrations, whereas > 100 fold higher concentrations of non-targeted TRAIL failed to reduce colony formation. Daily i.v. treatment with a low dose of anti-MCSP:TRAIL (0.14 mg/kg) resulted in a significant growth retardation of established A375 M xenografts. Anti-MCSP:TRAIL activity was further synergized by co-treatment with rimcazole, a σ-ligand currently in clinical trials for the treatment of various cancers.ConclusionsAnti-MCSP:TRAIL has promising pre-clinical anti-melanoma activity that appears to result from combined inhibition of tumorigenic MCSP-signaling and concordant activation of TRAIL-apoptotic signaling. Anti-MCSP:TRAIL alone, or in combination with rimcazole, may be of potential value for the treatment of malignant melanoma.

【 授权许可】

Unknown   
© de Bruyn et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.